Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects as many as one in 2500 individuals. We discovered that 43% of lupus patients have dramatically increased numbers of peripheral blood B cells that express the transcription factor ARID3a. Numbers of ARID3a+ B lymphocytes were associated with increased disease activity, suggesting that ARID3a might contribute to, or be a consequence of, disease activity. The underlying reasons for increased ARID3a expression in blood cells from lupus patients, and its association with disease activity are unclear. Recently, we observed that other peripheral blood cells, including plasmacytoid dendritic cells and neutrophils, also showed high levels of ARID3a expression in a subset of SLE blood samples compared to healthy controls. These cell types have been associated with production of Type I interferons, cytokines previously associated with inflammatory processes in lupus. Because other investigators showed that ARID3a is important for expression of a subset of B cell tropic viral genes, we hypothesized that ARID3a might be induced in normal innate immune responses. Our preliminary data support that hypothesis and indicate that ARID3a+ B cells express interferon alpha. Furthermore, inhibition of ARID3a in B lymphoblastoid cells also inhibits interferon alpha expression. We hypothesize that ARID3a will also be associated with interferon production in neutrophils and plasmacytoid dendritic cells, and that ARID3a+ neutrophils and/or dendritic cells will be associated with disease pathogenesis in SLE. Furthermore, we hypothesize that ARID3a expression is induced as a normal consequence of innate immune signals in hematopoietic stem cell progenitor populations, as well as in more mature hematopoietic cells. The proposed studies will define the associations between ARID3a expression and innate immune responses in neutrophils and plasmacytoid dendritic cells in lupus and healthy control samples, and will evaluate the requirement for ARID3a for interferon production using ARID3a knockdown experiments. Genes potentially regulated by ARID3a in innate immune signaling pathways will be identified. Finally, the consequences of innate immune responses in hematopoietic progenitors, and the association with ARID3a expression in those cells, will be evaluated. Together, the results of these experiments will fill an important gap in our understanding of regulatory responses in innate immunity, and will extend our understanding of ARID3a functions in immune cells. Ultimately, we expect these data to have broader impacts for our understanding of inflammatory responses associated with normal innate immunity and with autoimmune disease.